Producing radiopharmaceutical cold kits without lyophilization

Abstract

A method for making a radiopharmaceutical cold kit without lyophilization, comprising (1) providing a labeling ligand, a reducing agent, and a bulking agent, and at least one of an antioxidant and an exchange ligand, wherein each of said labeling ligand, reducing agent, bulking agent, antioxidant and exchange ligand is provided in a dry form; and (2) combining and mixing the labeling ligand, the reducing agent, the bulking agent, and at least one of the antioxidant and the exchange ligand to produce a dry powder mixture, wherein the wherein the dry powder mixture is produced without the use of a lyophilization step. The radiopharmaceutical cold kit comprising the dry powder mixture may be stored, or combined with a radionuclide such as Technetium-99m (99mTc).

What is claimed is: 
     
         1 . A method for making a radiopharmaceutical cold kit without lyophilization, comprising:
 providing a plurality of ingredients including a labeling ligand, a reducing agent, and a bulking agent, and at least one of an antioxidant and an exchange ligand, wherein each of said labeling ligand, reducing agent, bulking agent, antioxidant and exchange ligand is provided in a dry form; and   combining and mixing the labeling ligand, the reducing agent, the bulking agent, and at least one of the antioxidant and the exchange ligand to produce a final dry powder mixture, wherein the final dry powder mixture is produced without the use of a lyophilization step.   
     
     
         2 . The method of  claim 1 , further comprising sterilizing the final dry powder mixture, dispensing a desired quantity of the sterilized final dry powder mixture into a sterile vial forming a product vial, filling the product vial with an inert gas, and closing the product vial. 
     
     
         3 . The method of  claim 1 , wherein the combining and mixing step comprises:
 (1) combining and mixing the labeling ligand and the reducing agent in the dry form to produce a first dry mixture, (2) combining and mixing the first dry mixture and the antioxidant and/or the exchange ligand in the dry form to produce a second dry mixture, and (3) combining and mixing the second dry mixture and the bulking agent in the dry form to produce the final dry powder mixture.   
     
     
         4 . The method of  claim 1 , wherein the order of combining the plurality of ingredients from first to last is (1) the antioxidant, (2) the reducing agent, (3) the labeling ligand, and (4) the bulking agent. 
     
     
         5 . The method of  claim 1 , wherein the order of combining the plurality of ingredients from first to last is (1) a minor portion of the bulking agent, (2) the antioxidant, (3) the reducing agent, (4) the labeling ligand, and (5) the remaining portion of bulking agent. 
     
     
         6 . The method of  claim 1 , wherein the order of combining the plurality of ingredients from first to last is (1) the reducing agent, (2) the labeling ligand, (3) the bulking agent, and (4) the exchange ligand. 
     
     
         7 . The method of  claim 1 , wherein the order of combining the plurality of ingredients from first to last is (1) a minor portion of the exchange ligand, (2) the reducing agent, (3) the labeling ligand, (4) the bulking agent, and (5) the remaining portion of the exchange ligand. 
     
     
         8 . The method of  claim 1 , further comprising providing a buffer, wherein the final dry powder mixture comprises the buffer. 
     
     
         9 . The method of  claim 8 , wherein the order of combining the plurality of ingredients from first to last is (1) the reducing agent, (2) the buffer, (3) the antioxidant, and (4) the labeling ligand. 
     
     
         10 . The method of  claim 8 , wherein the order of combining the plurality of ingredients from first to last is (1) a minor portion of the labeling ligand, (2) the reducing agent, (3) the buffer, (4) the antioxidant, and (5) the remaining portion of the labeling ligand. 
     
     
         11 . The method of  claim 1 , wherein the radiopharmaceutical cold kit comprises an amount of the labeling ligand in a range of about 10 µg to about 25 mg. 
     
     
         12 . The method of  claim 1 , wherein the radiopharmaceutical cold kit comprises an amount of the exchange ligand in a range of about 0.1 mg to about 50 mg. 
     
     
         13 . The method of  claim 1 , wherein the radiopharmaceutical cold kit comprises an amount of the reducing agent in a range of about 0.1 mg to about 2 mg of Sn(II). 
     
     
         14 . The method of  claim 1 , wherein the radiopharmaceutical cold kit comprises an amount of the antioxidant in a range of about 0.1 mg to about 50 mg. 
     
     
         15 . The method of  claim 1 , wherein the radiopharmaceutical cold kit comprises an amount of the bulking agent in a range of about 5 mg to about 100 mg. 
     
     
         16 . The method of  claim 8 , wherein the radiopharmaceutical cold kit comprises an amount of the buffer in a range of about 1 mg to about 25 mg. 
     
     
         17 . The method of  claim 1 , wherein the labeling ligand is selected from the group consisting of Hydroxymethylenediphosphonic acid (HMDP, HDP), Methylene diphosphonate (MDP), ethane-I-hydroxy-I, 1- diphosphonate (EHDP), pyrophosphate, Ethylenediamine pentaacetic acid (DTPA, NA 5 DTPA or Na 3 CaDTPA), Mercaptoacetyltriglycine (MAG3, MAG 3 ), N,N-Ethylene-L,L-dicysteine (EC), L,L-ethyl cysteinate dimer (ECD), Dimercaptosuccinic acid (DMSA), N-(2,6-dimethylphenylcarbamoylmethyl)iminodiacetate (HIDA), (3-bromo-2,4,6-trimethylphenylcarbamoyl)methyliminodiacetic acid (mebrofenin, bromo-HIDA, Br-IDA), N-(2,6-diethylacetanilido) iminodiacetic acid (etifenin, EHIDA), diisopropyl iminodiacetic acid (disofenin, DISIDA), trimethylbromoiminoacetic acid (TBIDA), N-(2,6-diisopropylphenylcarbamoylmethyl) iminodiacetate (iprofenin, PIPIDA), Sodium thiosulphate pentahydrate (sulfur colloid), Stannous chloride dihydrate (tin colloid), human serum albumin (HSA) nanocolloid, HSA colloid, HSA microspheres, human immunoglobulin, macroaggregated albumin (MAA), TRODAT, d,1-Hexamethylpropylene amine oxime (d,1-HMPAO), methoxyisobutylisonitrile) (MIBI), 2-Ethoxy ethyl-3,12-dioxa-6,9-diphosphate tetradecane (tetrofosmin), hydrazinonicotimarnide tyr3 octreotate (HYNIC-TATE) acetate, hydrazinonicotinyl tyr3 octreotide (HYNIC-TOC), Ubiquicidin (UBI), glucoheptanate, phytate, cysteine, thiouracil, diethyldithiocarbamate, mercaptopyridine, mercaptopyrimidine, thiooxine, acetylacetone, pyridoxal, oxine, tropolone, and tetracycline. 
     
     
         18 . The method of  claim 1 , wherein the reducing agent is selected from the group consisting of stannous (II) chloride dihydrate, stannous tartrate, stannous citrate, stannous oxalate, stannous pyrophosphate, sodium borohydride, dithionite, and ferrous sulfate. 
     
     
         19 . The method of  claim 1 , wherein the antioxidant is selected from the group consisting of ascorbic acid and its salts, p-aminobenzoic acid and its salts, gentisic acid and its salts, citric acid and its salts, flavones, flavonoids, phenols, and polyphenols. 
     
     
         20 . The method of  claim 1 , wherein the exchange ligand is selected from the group consisting of sodium tartrate, potassium tartrate, sodium potassium tartrate, sodium citrate, potassium citrate, sodium potassium citrate, sodium gluconate, potassium gluconate, sodium potassium gluconate, tricine, or ethylenediaminetetraacetic acid (EDTA) or its salts. 
     
     
         21 . The method of  claim 1 , wherein the bulking agent is selected from the group consisting of sugar alcohols, monosaccharides, disaccharides, and calcium salts. 
     
     
         22 . The method of  claim 8 , wherein the buffer is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium potassium bicarbonate, sodium carbonate, potassium carbonate, sodium potassium carbonate, amino acids (e.g., glycine, cysteine), sodium bicarbonate, potassium bicarbonate, sodium potassium bicarbonate, sodium phosphate, potassium phosphate, sodium potassium phosphate, sodium pyrophosphate, potassium pyrophosphate, sodium potassium pyrophosphate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, sodium acetate, potassium acetate, sodium potassium acetate, and tricine. 
     
     
         23 . The method of  claim 1 , further comprising the step of adding an amount of a radionuclide to the final dry powder of the radiopharmaceutical cold kit, forming a radionuclide-ligand complex. 
     
     
         24 . The method of  claim 23 , wherein the radionuclide is Technetium-99m ( 99m Tc) and the radionuclide-ligand complex is a  99m Tc-ligand complex.